New process for the preparation of 2,4,5-
trifluorophenylacetic acid&#34;

ABSTRACT

The present invention relates to a new process for the preparation of 2,4,5-trifluorophenylacetic acid and salts thereof by means of new synthetic intermediates.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a process for the preparation of2,4,5-trifluorophenylacetic acid and salts thereof.

STATE OF THE ART

Fluorophenylacetic acids are useful intermediates for the preparation ofvarious pharmacologically active compounds. In particulartrifluorophenylacetic acids are used in the preparation of inhibitors ofthe dipeptidyl peptidase-4 enzyme. These medicines are useful intreating diabetes, in particular type 2 diabetes (see for example WO97/40832; WO 98/19998; U.S. Pat. No. 5,939,560; Bioorg. Med. Chem.Lett., 6, 1163-1166 (1996); Bioorg. Med. Chem. Lett., 6, 2745-2748(1996))

One of these active ingredients is Sitagliptin, available commerciallyunder the brand name Januvia, which uses 2,4,5-trifluorophenylaceticacid as a key intermediate for its synthesis.

US 20040068141 claims a process for the preparation offluorophenylacetic acids starting from aromatic halides according to themethod described in diagram 1 (X represents chlorine, bromine oriodine):

The first step however requires the use of large quantities of coppersalts, with obvious problems of extraction and disposal of the heavymetal, and the aromatic halide used often has elevated costs.

U.S. Pat. No. 5,306,833 claims a process for the preparation ofphenylacetic acids substituted on the aromatic ring with electron donorgroups by reduction of corresponding mandelic acids. In particularp-hydroxyphenylacetic acid is obtained starting from sodiump-hydroxymandelate and p-methoxyphenylacetic acid is obtained startingfrom sodium p-methoxymandelate. However such method is applicable onlyto electron rich substrates and does not work with substrates withelectron attractor substitutes such as fluorine.

In the application WO2008078350 a process is described composed ofvarious steps of synthesis for the preparation of fluorophenylaceticacids and their derivatives, in particular of2,4,5-trifluorophenylacetic acid, starting from corresponding mandelicacids.

SUMMARY OF THE INVENTION

The problem addressed by the present invention is that of makingavailable an alternative process for the preparation of2,4,5-trifluorophenylacetic acid and salts thereof, by means of newsynthetic intermediates, which makes it possible to at least partiallyovercome the drawbacks presented above in relation to the prior art.

Such problem is resolved by a process of synthesis of2,4,5-trifluorophenylacetic acid as delineated in the appended claims,the definitions of which form an integral part of this description.

Further characteristics and advantages of the process according to theinvention will be evident from the description below of its preferredembodiments made by way of non-limiting examples.

BRIEF DESCRIPTION OF THE FIGURES (OR DRAWINGS)

By way of example:

FIG. 1 shows a general diagram of the process according to the presentinvention.

FIG. 2 shows the ¹H-NMR spectrum of the compound of formula (IV) inwhich X is Cl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of2,4,5-trifluorophenylacetic acid of formula (I) or a salt thereof:

-   -   comprising the following steps:    -   (a) halogenation of the compound of formula (VII):

-   -   in which X is a halogen atom,    -   to give the compound of formula (V):

-   -   in which X and X′ are independently halogen atoms,    -   and/or the compound of formula (VI):

-   -   in which X and X′ are independently halogen atoms,    -   (b) dehydrohalogenation of the compound/s obtained in the        previous step to give the compound of formula (IV):

-   -   in which X is a halogen atom;    -   (c) conversion of the compound obtained in the previous step        into the compound of formula (II):

-   -   in which R is a linear or branched C1-C5 alkyl or is an aryl or        benzyl group; and/or into the compound of formula (III):

-   -   in which X is a halogen atom and R is a linear or branched C1-C5        alkyl or is an aryl or benzyl group;    -   (d) hydrolysis of the compound/s obtained in the previous step        to give the compound of formula (I) or salts thereof:        or, alternatively to the steps (c) and (d) the following step:    -   (e) direct hydrolysis of the compound of formula (IV) obtained        in the step (b) to give the compound of formula (I) or salts        thereof.

For compound of formula (III):

both that having the Cis (Z) configuration and that having the Trans (E)configuration are meant.

According to a preferred embodiment the steps (b) and (c) may be carriedout consecutively therefore without the isolation of the compound offormula (IV).

According to a further preferred embodiment the steps (c) and (d) may becarried out consecutively without the isolation of the compound offormula (II) and/or of the compound of formula (III). In addition, steps(b),(c) and (d) may be carried out consecutively without the need toisolate the intermediates of formula (IV), (III) and (II).

The process according to the present invention may also comprise thefurther step of acylation of 1,2,4-trifluorobenzene of formula (VIII) togive the compound of formula (VII):

in which X is a halogen atom.

By atom of halogen in all the intermediate compounds of the presentinvention an atom chosen from fluorine, chlorine, bromine or iodine ismeant.

In all the intermediate compounds the two atoms of halogen X and X′ areindependent, that is to say, may be the same or different.

According to a preferred embodiment the process of the present inventionis conveniently carried out using intermediate compounds of formula(III), (IV), (V), (VI) and (VII) in which X is a chlorine atom.

According to a preferred embodiment the process of the present inventionmay be carried out using compounds of formula (V) and (VI) in which X′is a chlorine atom.

According to a more preferred embodiment the process of the presentinvention may be carried out using compounds of formula (V) and (VI) inwhich both X and X′ are a chlorine atom.

The process of the present invention may utilise compounds of formula(III) and (II) in which R is a linear or branched C1-C5 alkyl, thereforechosen from the group comprising methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl,2-ethylpropyl, isopentyl, 2,2-dimethylpropyl. Preferably the process ofthe present invention is performed with R equal to methyl or ethyl.

The process of the present invention may also utilise compounds offormula (III) and (II) in which R is an aryl or benzyl, thus comprisingfor example phenyl or naphthyl.

The step (a) of the present invention is a halogenation reactionincluding for example a fluorination or an iodination, chlorinations andbrominations being preferred. Such latter may be conveniently conductedwith PCl₅, POCl₃, PBr₃. The halogenations are preferably carried out inorganic solvent such as THF, Dioxane, DMF, NMP, DMSO, benzene, toluene,chlorobenzene, nitrobenzene, fluoro-benzenes, xylenes, fluoro-benzenebeing preferred.

The step (b) of dehydrohalogenation and/or the step (c) of alkoxylationof the process of the present invention may be conducted with hydroxidesor alkoxides of various alkaline or alkaline-earth metals, such as forexample NaOH or KOH. In particular KOH or a linear or branched C1-C5alkaline or earth-alkaline alkoxide may preferably be used.

Said steps of synthesis are conducted in the presence of an organicsolvent such as THF, Dioxane, DMF, NMP, DMSO, dimethoxyethane andalcohols, preferably such solvent is a linear or branched C1-C5 alcohol.Preferably it is possible to use Methanol and Ethanol.

According to a variation of the process according to the presentinvention, the intermediate of formula (IV) may be converted directly,according to step (e), to a product of formula (I). To such purpose anacid hydrolysis of the compound of formula (IV) is preferably used,which is preferably carried out by means of concentrated sulphuric acid.

The following compounds are new intermediates of the process ofsynthesis according to the present invention: intermediate of formula(II)

in which R is a linear or branched C3-C5 alkyl or is an aryl or benzylgroup;intermediate of formula (III)

in which X is a halogen atom and R is a linear or branched C1-C5 alkylor is an aryl or benzyl group;intermediate of formula (IV):

in which X is a halogen atom;intermediate of formula (V):

in which X and X′ are independently halogen atoms,intermediate of formula (VI):

in which X and X′ are independently halogen atoms,intermediate of formula (VII):

in which X is Fluorine or Iodine.

The compounds of formula (III), (IV), (V), (VI) and (VII) in which X isa chlorine atom are preferred.

The compounds of formula (V) and (VI) in which X′ is a chlorine atom arealso preferred.

The compounds of formula (V) and (VI) in which both X and X′ arechlorine atoms are even more preferred.

The intermediate compounds as described above are thus conveniently usedfor the preparation of the compound of formula (I) or salts thereof.

The 2,4,5-trifluorophenylacetic acid of formula (I) or the salts thereofprepared according to the process of the present invention may beconveniently used for the preparation of Sitagliptin according to themethods of the prior art.

EXPERIMENTAL PART Example 1 Synthesis of2-Chloro-1-(2,4,5-trifluorophenyl)ethanone of formulaVII—X=Cl—Illustrative of the Invention According to Preferred AspectsSynthesis Diagram

A mixture of 1,2,4-trifluorobenzene (15 ml, 144 mmol) of formula (VIII),chloroacetyl chloride (11.5 ml, 145 mmol) and aluminium trichloride(38.3 g, 285 mmol) was stirred at 70° C. for 16 h. It was thenneutralised with aqueous saturated Na₂CO₃. The resulting mixture wasextracted with Et₂O (3×30 ml) and the combined organic phases werewashed with an aqueous solution of NaHCO₃ (30 ml) and brine (30 ml),then dried with MgSO₄ and concentrated in the rotary evaporator. Theresidue was further purified by sublimation obtaining 27.1 g ofcolourless crystalline product with a molar yield of 93%.

Example 2 Synthesis of 1,2,4-trifluoro-5-(1,1,2-trichloroethyl)benzeneof Formula V—X=Cl, X′=Cl and1-[(E/Z)-1,2-dichloroethenyl]-2,4,5-trifluorobenzene of formula VI—X=Cl,X′=Cl Step (a) of the Invention Halogenation by ChlorinationIllustrative of the Invention According to Preferred Aspects SynthesisDiagram

A mixture of 2-Chloro-1-(2,4,5-trifluorophenyl)ethanone of formula(VII—X=Cl) (5 g, 24 mmol) and PCl₅ (15 g, 72 mmol) in fluorobenzene (20ml) was stirred at 80° C. for h. The resulting mixture was neutralisedwith an aqueous saturated solution of Na₂CO and extracted with pentane(3×30 ml). The combined organic phases were washed with an aqueoussolution of NaHCO₃ (30 ml) and brine (30 ml), then dried with MgSO₄ andconcentrated in the rotary evaporator. 5.7 g of a colourless oilcontaining 1,2,4-trifluoro-5-(1,1,2-trichloroethyl)benzene of formulaV—X=Cl, X′=Cl (40%, estimated via GC) and a mixture of geometric isomersE/Z of 1-[1,2-dichloroethenyl]-2,4,5-trifluorobenzene of formulaVI—X=Cl, X′=Cl (60%, estimated via GC) were obtained. The conversion ofthe starting compound of formula VII—X=Cl into the aforesaid threecompounds proved to be quantitative.

Example 3 Synthesis of (E/Z)-1-Chloro-2-(2,4,5-trifluorophenyl)ethenylethyl ether of Formula III—X=Cl, R=Et and Ethyl Esther of the2,4,5-trifluorophenylacetic acid of Formula II—R=Et One-Pot Step (b)+(c)of the Invention: Dehydrohalogenation+Alkoxylation Illustrative of theInvention According to Preferred Aspects Synthesis Diagram

The mixture of chlorination products of example 2 (118 mg, 0.4 mmol) andEtOH (0.23 ml, 4 mmol) was added to a suspension of KOH (112 mg, 2 mmol)in toluene (2 ml). The resulting mixture was stirred under Argon at 80°C. for 4 hours. HCl 1 M (2 ml) and Et₂O (2 ml) were added at the end.The organic phase was concentrated to dryness. GC analysis of themixture with the internal standard (Tetradecane) shows the 41% molarformation of ethyl esther of the 2,4,5-trifluorophenylacetic acid offormula II—R=Et and 20% molar of mixture of geometric isomers E/Z of1-Chloro-2-(2,4,5-trifluorophenyl)ethenyl ethyl ether of formulaIII—X=Cl, R=Et.

The 1H-NMR (300 MHz, CDCl₃) spectrum of the compound of formula IV—X=Clis shown: δ=7.18-7.31 (m, 1H), 6.88-7.07 (m, 1H) (see FIG. 2).

Example 4 Synthesis of the 2,4,5-trifluorophenylacetic acid (I) One-PotStep (b)+(c)+(d) According to the Invention:Dehydrohalogenation+Alkoxylation+Hydrolysis, Illustrative of theInvention According to Preferred Aspects Synthesis Diagram

The mixture of chlorination products of example 2 (118 mg, 0.4 mmol) andEtOH (0.23 ml, 4 mmol) was added to a suspension of KOH (112 mg, 2 mmol)in toluene (2 ml) and the resulting mixture was stirred under Argon at80° C. for 4 hours. The solvent was removed under a vacuum and asolution of NaOH 2 M (2 ml) was added at the end. The mixture wasagitated at 60° C. observing the complete hydrolysis of ethyl esther ofthe 2,4,5-trifluorophenylacetic acid of formula II—R=Et and theformation of the 2,4,5-trifluorophenylacetic acid of formula (I).

Example 5 Synthesis of the 2,4,5-trifluorophenylacetic acid of Formula(I) Step/Variation (e) of the Invention: Acid Hydrolysis, Illustrativeof the Invention Synthesis Diagram

50 ml of concentrated sulphuric acid was added to1-chloroethynyl-2,4,5-trifluorobenzene of formula IV, X=Cl and themixture heated to 100° C. and left to stir for 1 hour. 50 ml of MTBE and100 ml of water were then added. The phases were separated and theaqueous phase was re-extracted with 2×50 ml of MTBE. The combinedorganic phases were counter extracted with 3×50 ml of aqueous NaHCO₃ andput to one side. The three aqueous phases of NaHCO₃ were recombined andthe resulting phase was acidified with hydrochloric acid and thenextracted with 3×50 ml of MTBE. The organic phases were concentrated toa residue obtaining 0.25 g of 2,4,5-trifluorophenylacetic acid offormula (I) with a molar yield of 25%.

On the basis of the description above, a person skilled in the art mayappreciate the advantages offered by the process according to thepresent invention; in particular the process of the present inventionmay lead to a 2,4,5-trifluorophenylacetic acid product in just two stepsof synthesis which, among other things, entail very low cost industrialreactions. Both the operativity and the cost of the raw materials of theprocess according to the invention is extremely limited making suchprocess of great interest for its application on an industrial scale.

1. Process for the preparation of 2,4,5-trifluorophenylacetic acid offormula (I) or a salt thereof:

comprising the following steps: (a) halogenation of the compound offormula (VII):

in which X is a halogen atom, to give the compound of formula (V):

in which X and X′ are independently halogen atoms, and/or the compoundof formula (VI):

in which X and X′ are independently halogen atoms, (b)dehydrohalogenation of the compound/s obtained in the previous step togive the compound of formula (IV):

in which X is a halogen atom; (c) conversion of the compound obtained inthe previous step into the compound of formula (II):

in which R is a linear or branched C1-C5 alkyl or is an aryl or benzylgroup; and/or into the compound of formula (III):

in which X is a halogen atom and R is a linear or branched C1-C5 alkylor is an aryl or benzyl group; (d) hydrolysis of the compound/s obtainedin the previous step to give the compound of formula (I) or saltsthereof: or, alternatively to the steps (c) and (d) the following step:(e) direct hydrolysis of the compound of formula (IV) obtained in thestep (b) to give the compound of formula (I) or salts thereof. 2.Process according to the claim 1 in which the steps (b) and (c) arecarried out consecutively without the isolation of the compound offormula (IV).
 3. Process according to claim 1 in which the steps (c) and(d) are carried out consecutively without the isolation of the compoundof formula (II) and/or of the compound of formula (III).
 4. Processaccording to claim 1 in which the steps (b), (c) and (d) are carried outconsecutively without the isolation of the compound of formula (IV),(II) and/or of the compound of formula (III).
 5. Process according toclaim 1 comprising the further step of acylation of1,2,4-trifluorobenzene of formula (VIII) to give the compound of formula(VII):

in which X is a halogen atom.
 6. Process according to claim 1, in whichin the compounds of formula (III), (IV), (V), (VI) and (VII) X is achlorine atom.
 7. Process according to claim 1 in which in the compoundsof formula (V) and (VI) X′ is a chlorine atom.
 8. Process according toclaim 1 in which in the compounds of formula (II) and (III) R is Methylor Ethyl.
 9. Process according to claim 1 in which the step (a) isperformed with PCl₅, POCl₃ or PBr₃.
 10. Process according to claim 1 inwhich the step (b) and/or the step (c) are carried out with KOH or analkaline or earth alkaline C1-C5 linear or branched alkoxide. 11.Process according to the claim 10 in which the step (b) and/or the step(c) are carried out in presence of a linear or branched C1-C5 alcoholsolvent.
 12. The following compounds: intermediate of formula (II)

in which R is a linear or branched C3-C5 alkyl or is an aryl or benzylgroup; intermediate of formula (III)

in which X is a halogen atom and R is a linear or branched C1-C5 alkylor is an aryl or benzyl group; intermediate of formula (IV):

in which X is a halogen atom; intermediate of formula (V):

in which X and X′ are independently halogen atoms, intermediate offormula (VI):

in which X and X′ are independently halogen atoms, intermediate offormula (VII):

in which X is Fluorine or Iodine.
 13. Compound according to the claim 12in which in the compounds of formula (III), (IV), (V), (VI) and (VII) Xis a chlorine atom.
 14. Compound according to claim 12 in which in thecompounds of formula (V) and (VI) X′ is a chlorine atom.
 15. Compoundaccording to claim 12 in which in the compounds of formula (V) and (VI)both X and X′ are a chlorine atom.
 16. Use of the compounds according toclaim 12 for the preparation of the compound of formula (I) or saltsthereof.
 17. Use of the compound of formula (I) or salts thereofprepared with the process according to claim 1 for the preparation ofSitagliptin.